Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

GADD45A (growth arrest and DNA-damage-inducible, alpha)

Written2014-06Sirma Damla User, Mesut Muyan
Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

Abstract Growth Arrest and DNA-damage-inducible, alpha (GADD45α) is a member of the GADD family proteins that also include GADD45β and GADD45γ. The highly conserved GADD45 proteins are small (18 kDa) and primarily localized in the nucleus. The GADD45 proteins acting as sensors of environmental and physiological stress interact with and/or modulate the activities of partner proteins involved in cell cycle, cell survival, apoptosis, maintenance of genomic stability and DNA repair. GADD45 proteins also act as sensors of oncogenic stress in the initiation of tumors and in tumor responses to different therapeutics. The expression of GADD45α in response to DNA damage is mediated by p53-dependent and p53-independent mechanisms, the latter which involves Wilms tumor 1 (WT1) protein. GADD45α subsequently inhibits G2/M transition of cell cycle and induces apoptosis. GADD45α also has a role in DNA-demethylation to promote genome stability. In many malignancies, GADD45α levels are down-regulated, likely allowing tumor cells to escape from senescence and apoptosis. Novel approaches are therefore being developed to regulate GADD45α levels to combat malignancies.

(Note : for Links provided by Atlas : click)

Identity

Alias_namesDDIT1
growth arrest and DNA-damage-inducible
Alias_symbol (synonym)GADD45
HGNC (Hugo) GADD45A
LocusID (NCBI) 1647
Atlas_Id 339
Location 1p31.3  [Link to chromosome band 1p31]
Location_base_pair Starts at 68150860 and ends at 68154021 bp from pter ( according to hg19-Feb_2009)  [Mapping GADD45A.png]
 
Fusion genes
(updated 2016)
GADD45A (1p31.3) / FRA10AC1 (10q23.33)

DNA/RNA

 
  Human GADD45α located on chromosome 1 is on the forward strand. It consists of four exons represented as boxes and introns shown as lines. Darker grey boxes indicate the open reading frame (ORF) of 498 base pairs (bp). The first methionine (ATG) and the stop codon (TGA) of ORF are marked. The length of each exon and intron is shown in base pairs.
Description The human GADD45α is localized on chromosome 1 and comprises four exons (NCBI, 2014).
Transcription Depending on the splicing of the GADD45α pre-mRNA, there are three mRNA variants.
Pseudogene Homologous sequence on chromosome 12q may be a retro-pseudogene (Papathanasiou et al., 1991).

Protein

Note Based on mRNA sequences, it is predicted that there are three isoforms of GADD45α protein (NCBI, 2014). While the isoform 1 utilizes 498 bp ORF encoding 165 amino acids (aa)-long protein (protein ID: NP_001915.1), the absence of the second in-frame exon in the isoform 2 results in a 396 bp ORF giving rise to a 131 aa-long protein (protein ID: NP_001186670.1). In the isoform 3, the second and third exons partially exist forming a 183 bp mRNA that encodes a 60 aa-long protein (protein ID: NP_001186671.1).
Description GADD45α protein is a member of the GADD family that includes GADD45β and GADD45γ. Forming a homodimer as well as heterodimers with other family members, GADD45α is involved in the maintenance of genomic integrity, growth arrest and apoptosis (Rosemary Siafakas and Richardson, 2009; Sytnikova et al., 2011) through interactions with various proteins including Cdc2 protein kinase, p21Waf1/Cip1 protein, core histone proteins, proliferating cell nuclear antigen (PCNA) and MTK/MEKK4 (Zerbini and Libermann, 2005; Zhan, 2005; Rosemary Siafakas and Richardson, 2009; Johnson et al., 2013). GADD45α also acts as an RNA binding protein (Sytnikova et al., 2011). Ubiquitination appears to be involved in the turnover of GADD45α (Leung et al., 2001).
Expression Protein levels of GADD45α varies during the cell cycle, the highest being in G1 phase and the lowest in S phase (Zhan, 2005; Rosemary Siafakas and Richardson, 2009). The expression of GADD45α is regulated by p53-dependent and p53-independent mechanisms. The p53-dependent pathway involves the direct binding of p53 to a cognate response element located on the third intron of GADD45α. Whereas, in the p53-independent signaling route, p53 modulates GADD45α expression by interacting with WT1, a transcription factor and a tumor suppressor, bound on GC-rich motifs of the GADD45α promoter (Zhan, 2005; Johnson et al., 2013). Rapid and transient expression of GADD45α can be induced by DNA damaging agents including UV (p53-independent), ionizing radiation (p53-dependent), methylmethane sulfonate (MMS), nitrogen mustard, melphalan, hydrogen peroxide and hypoxia as well as by the withdrawal of growth factors (Hollander and Fornace, 2002; Zhan, 2005; Rosemary Siafakas and Richardson, 2009). GADD45α expression is also activated by breast cancer 1, early onset, (BRCA1) in various cell lines (Harkin et al., 1999).
Localisation GADD45α, as other members of GADD family proteins, is predominantly localized in the nucleus (Zhan, 2005; Rosemary Siafakas and Richardson, 2009). In glioblastoma and breast tumors, GADD45α is also observed to localize in the cytoplasm (Reddy et al., 2008; Tront et al., 2013).
Function The maintenance of genome integrity is essential to prevent the development of cancer, which is associated with genomic instability. GADD45α plays an important role in maintaining genomic integrity by promoting nucleotide-excision repair (NER), cell cycle arrest and apoptosis (Hollander and Fornace, 2002; Barreto et al., 2007; Sytnikova et al., 2011). GADD45α mediates NER by binding to repair endonuclease xeroderma pigmentosum G (XPG) protein (Hollander and Fornace, 2002; Barreto et al., 2007; Sytnikova et al., 2011). While the disruption of Cdc2/Cyclin B1 interactions by GADD45α is critical for the blockage of G2/M transition (Zhan et al., 1999; Rosemary Siafakas and Richardson, 2009), the activation of c-Jun N-terminal kinase (JNK) as a result of the interaction of GADD45α with mitogen-activated protein three kinase (MTK1) induces apoptosis (Zerbini and Libermann, 2005). GADD45α is also reported to repress cell migration and invasion by suppressing β-catenin signaling through stress-mediated p38 mitogen activated protein kinase (MAPK) pathway (Hildesheim et al., 2004).
Homology The human GADD45α shows 90% aa identity to GADD45α of other species including rhesus monkey, domestic cat, hamster, mouse and rat (Rosemary Siafakas and Richardson, 2009). In addition, there is a nearly 50% aa identity among GADD45α and other GADD45 proteins (Rosemary Siafakas and Richardson, 2009). The RNA-binding domain of GADD45α displays high aa homology to many RNA binding proteins that includes ribosomal proteins L7a, S12 and L30e (Sytnikova et al., 2011; Tian and Locker, 2013).

Implicated in

Note
Entity Colorectal carcinoma
Note In primary colorectal carcinoma tissue samples grouped according to tumor staging (group 1: restricted to gut; group 2: restricted to gut but signs of malignancy on lymph nodes are present; group 3: in addition to group 2 characteristics, metastasis to distant tissue is present), it was observed that GADD45α expression decreases as staging increases. Whereas, GADD45α expression in close proximity or distant tissues remains unchanged (Štorcelová et al., 2013).
  
Entity Breast cancer
Note Intracellular level of GADD45α assessed by immunocytochemistry is reported to positively correlate with the presence of estrogen and progesterone receptors in primary breast cancer samples (Tront et al., 2013). It appears that GADD45α levels are higher in Luminal A (ER+, PR+, HER2-) and Luminal B (ER+, PR+, HER2+) subgroups of tumors than HER2+ (HER2+, ER-,PR-) and Triple Negative (ER-, PR-, HER2-) subgroups (Tront et al., 2013).
  
Entity Gastric cardia adenocarcinoma
Note Relative mRNA expression evaluated by qPCR of gastric cardia adenocarcinoma (GCA) samples suggests that the expression of GADD45α is repressed compared to that of neighboring normal tissue samples. Based on TNM staging, GADD45α mRNA levels were found to be higher in Stage I and Stage II patient samples than Stage III and Stage IV patient samples. Higher degree of methylation of the GADD45α gene promoter appears to be one reason for the decreased expression of GADD45α in GCA. There were no other correlation between GADD45α mRNA levels and clinicopathological characteristics (Guo et al., 2013).
  
Entity Glioblastoma
Note In diffuse-infiltrating astrocytomas, the expression of GADD45α assessed by qPCR shows variations depending on tumor grading. It appears that GADD45α is expressed at higher levels in glioblastoma (GBM; WHO grade IV) compared to astrocytoma (DA; WHO grade II) or to anaplastic astrocytoma (AP; WHO grade III) (Reddy et al., 2008).
  

Bibliography

GADD45a promotes epigenetic gene activation by repair-mediated DNA demethylation.
Barreto G, Schafer A, Marhold J, Stach D, Swaminathan SK, Handa V, Doderlein G, Maltry N, Wu W, Lyko F, Niehrs C.
Nature. 2007 Feb 8;445(7128):671-5. Epub 2007 Jan 31.
PMID 17268471
 
Methylation-mediated repression of GADD45a and GADD45G expression in gastric cardia adenocarcinoma.
Guo W, Dong Z, Guo Y, Chen Z, Kuang G, Yang Z.
Int J Cancer. 2013 Nov;133(9):2043-53. doi: 10.1002/ijc.28223. Epub 2013 May 25.
PMID 23616123
 
Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1.
Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C, Christians FC, Ellisen LW, Maheswaran S, Oliner JD, Haber DA.
Cell. 1999 May 28;97(5):575-86.
PMID 10367887
 
GADD45a regulates matrix metalloproteinases by suppressing DeltaNp63alpha and beta-catenin via p38 MAP kinase and APC complex activation.
Hildesheim J, Belova GI, Tyner SD, Zhou X, Vardanian L, Fornace AJ Jr.
Oncogene. 2004 Mar 11;23(10):1829-37.
PMID 14647429
 
Genomic instability, centrosome amplification, cell cycle checkpoints and GADD45a.
Hollander MC, Fornace AJ Jr.
Oncogene. 2002 Sep 9;21(40):6228-33. (REVIEW)
PMID 12214253
 
The involvement of WT1 in the regulation of GADD45a in response to genotoxic stress.
Johnson D, Hastwell PW, Walmsley RM.
Mutagenesis. 2013 Jul;28(4):393-9. doi: 10.1093/mutage/get015. Epub 2013 Mar 9.
PMID 23476008
 
PKCdelta-dependent deubiquitination and stabilization of Gadd45 in A431 cells overexposed to EGF.
Leung CH, Lam W, Zhuang WJ, Wong NS, Yang MS, Fong WF.
Biochem Biophys Res Commun. 2001 Jul 13;285(2):283-8.
PMID 11444839
 
Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C.
Papathanasiou MA, Kerr NC, Robbins JH, McBride OW, Alamo I Jr, Barrett SF, Hickson ID, Fornace AJ Jr.
Mol Cell Biol. 1991 Feb;11(2):1009-16.
PMID 1990262
 
Novel glioblastoma markers with diagnostic and prognostic value identified through transcriptome analysis.
Reddy SP, Britto R, Vinnakota K, Aparna H, Sreepathi HK, Thota B, Kumari A, Shilpa BM, Vrinda M, Umesh S, Samuel C, Shetty M, Tandon A, Pandey P, Hegde S, Hegde AS, Balasubramaniam A, Chandramouli BA, Santosh V, Kondaiah P, Somasundaram K, Rao MR.
Clin Cancer Res. 2008 May 15;14(10):2978-87. doi: 10.1158/1078-0432.CCR-07-4821.
PMID 18483363
 
Growth arrest and DNA damage-45 alpha (GADD45alpha).
Rosemary Siafakas A, Richardson DR.
Int J Biochem Cell Biol. 2009 May;41(5):986-9. doi: 10.1016/j.biocel.2008.06.018. Epub 2008 Aug 5. (REVIEW)
PMID 18760377
 
Expression of cell cycle regulatory factors hus1, GADD45a, rb1, cdkn2a and mre11a correlates with expression of clock gene per2 in human colorectal carcinoma tissue.
Storcelova M, Vician M, Reis R, Zeman M, Herichova I.
Mol Biol Rep. 2013 Nov;40(11):6351-61. doi: 10.1007/s11033-013-2749-2. Epub 2013 Sep 24.
PMID 24062075
 
GADD45a is an RNA binding protein and is localized in nuclear speckles.
Sytnikova YA, Kubarenko AV, Schafer A, Weber AN, Niehrs C.
PLoS One. 2011 Jan 7;6(1):e14500. doi: 10.1371/journal.pone.0014500.
PMID 21249130
 
Gadd45 in the liver: signal transduction and transcriptional mechanisms.
Tian J, Locker J.
Adv Exp Med Biol. 2013;793:69-80. doi: 10.1007/978-1-4614-8289-5_5. (REVIEW)
PMID 24104474
 
GADD45a levels in human breast cancer are hormone receptor dependent.
Tront JS, Willis A, Huang Y, Hoffman B, Liebermann DA.
J Transl Med. 2013 May 24;11:131. doi: 10.1186/1479-5876-11-131.
PMID 23706118
 
Life and death in cancer. GADD45 alpha and gamma are critical regulators of NF-kappaB mediated escape from programmed cell death.
Zerbini LF, Libermann TA.
Cell Cycle. 2005 Jan;4(1):18-20. Epub 2005 Jan 11.
PMID 15613850
 
Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45.
Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, Fornace AJ Jr.
Oncogene. 1999 May 6;18(18):2892-900.
PMID 10362260
 
GADD45a, a p53- and BRCA1-regulated stress protein, in cellular response to DNA damage.
Zhan Q.
Mutat Res. 2005 Jan 6;569(1-2):133-43. (REVIEW)
PMID 15603758
 

Citation

This paper should be referenced as such :
SD User, M Muyan
GADD45A (growth arrest, DNA-damage-inducible, alpha)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(3):164-167.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/GADD45AID339ch1p31.html


External links

Nomenclature
HGNC (Hugo)GADD45A   4095
Cards
AtlasGADD45AID339ch1p31
Entrez_Gene (NCBI)GADD45A  1647  growth arrest and DNA damage inducible alpha
AliasesDDIT1; GADD45
GeneCards (Weizmann)GADD45A
Ensembl hg19 (Hinxton)ENSG00000116717 [Gene_View]  chr1:68150860-68154021 [Contig_View]  GADD45A [Vega]
Ensembl hg38 (Hinxton)ENSG00000116717 [Gene_View]  chr1:68150860-68154021 [Contig_View]  GADD45A [Vega]
ICGC DataPortalENSG00000116717
TCGA cBioPortalGADD45A
AceView (NCBI)GADD45A
Genatlas (Paris)GADD45A
WikiGenes1647
SOURCE (Princeton)GADD45A
Genetics Home Reference (NIH)GADD45A
Genomic and cartography
GoldenPath hg19 (UCSC)GADD45A  -     chr1:68150860-68154021 +  1p31.2   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)GADD45A  -     1p31.2   [Description]    (hg38-Dec_2013)
EnsemblGADD45A - 1p31.2 [CytoView hg19]  GADD45A - 1p31.2 [CytoView hg38]
Mapping of homologs : NCBIGADD45A [Mapview hg19]  GADD45A [Mapview hg38]
OMIM126335   
Gene and transcription
Genbank (Entrez)AK314991 AM393439 BC011757 BU629410 DQ008445
RefSeq transcript (Entrez)NM_001199741 NM_001199742 NM_001924
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)GADD45A
Cluster EST : UnigeneHs.80409 [ NCBI ]
CGAP (NCI)Hs.80409
Alternative Splicing GalleryENSG00000116717
Gene ExpressionGADD45A [ NCBI-GEO ]   GADD45A [ EBI - ARRAY_EXPRESS ]   GADD45A [ SEEK ]   GADD45A [ MEM ]
Gene Expression Viewer (FireBrowse)GADD45A [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1647
GTEX Portal (Tissue expression)GADD45A
Protein : pattern, domain, 3D structure
UniProt/SwissProtP24522   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP24522  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP24522
Splice isoforms : SwissVarP24522
PhosPhoSitePlusP24522
Domains : Interpro (EBI)GADD45    L30e-like    Ribosomal_L7Ae/L30e/S12e/Gad45   
Domain families : Pfam (Sanger)Ribosomal_L7Ae (PF01248)   
Domain families : Pfam (NCBI)pfam01248   
Conserved Domain (NCBI)GADD45A
DMDM Disease mutations1647
Blocks (Seattle)GADD45A
PDB (SRS)2KG4   
PDB (PDBSum)2KG4   
PDB (IMB)2KG4   
PDB (RSDB)2KG4   
Structural Biology KnowledgeBase2KG4   
SCOP (Structural Classification of Proteins)2KG4   
CATH (Classification of proteins structures)2KG4   
SuperfamilyP24522
Human Protein AtlasENSG00000116717
Peptide AtlasP24522
HPRD00528
IPIIPI00029104   IPI00847452   IPI00921153   IPI00513748   
Protein Interaction databases
DIP (DOE-UCLA)P24522
IntAct (EBI)P24522
FunCoupENSG00000116717
BioGRIDGADD45A
STRING (EMBL)GADD45A
ZODIACGADD45A
Ontologies - Pathways
QuickGOP24522
Ontology : AmiGOregulation of cyclin-dependent protein serine/threonine kinase activity  activation of MAPKKK activity  core promoter binding  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  DNA repair  negative regulation of protein kinase activity  apoptotic process  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  cell cycle arrest  centrosome cycle  signal transduction in response to DNA damage  positive regulation of apoptotic process  positive regulation of JNK cascade  cellular response to mechanical stimulus  cellular response to ionizing radiation  mitotic cell cycle arrest  positive regulation of p38MAPK cascade  positive regulation of reactive oxygen species metabolic process  
Ontology : EGO-EBIregulation of cyclin-dependent protein serine/threonine kinase activity  activation of MAPKKK activity  core promoter binding  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  DNA repair  negative regulation of protein kinase activity  apoptotic process  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  cell cycle arrest  centrosome cycle  signal transduction in response to DNA damage  positive regulation of apoptotic process  positive regulation of JNK cascade  cellular response to mechanical stimulus  cellular response to ionizing radiation  mitotic cell cycle arrest  positive regulation of p38MAPK cascade  positive regulation of reactive oxygen species metabolic process  
Pathways : BIOCARTACell Cycle: G2/M Checkpoint [Genes]    ATM Signaling Pathway [Genes]    p53 Signaling Pathway [Genes]    Hypoxia and p53 in the Cardiovascular system [Genes]   
Pathways : KEGGMAPK signaling pathway    FoxO signaling pathway    Cell cycle    p53 signaling pathway   
REACTOMEP24522 [protein]
REACTOME PathwaysR-HSA-6804114 [pathway]
NDEx NetworkGADD45A
Atlas of Cancer Signalling NetworkGADD45A
Wikipedia pathwaysGADD45A
Orthology - Evolution
OrthoDB1647
GeneTree (enSembl)ENSG00000116717
Phylogenetic Trees/Animal Genes : TreeFamGADD45A
HOVERGENP24522
HOGENOMP24522
Homologs : HomoloGeneGADD45A
Homology/Alignments : Family Browser (UCSC)GADD45A
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGADD45A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GADD45A
dbVarGADD45A
ClinVarGADD45A
1000_GenomesGADD45A 
Exome Variant ServerGADD45A
ExAC (Exome Aggregation Consortium)GADD45A (select the gene name)
Genetic variants : HAPMAP1647
Genomic Variants (DGV)GADD45A [DGVbeta]
DECIPHER (Syndromes)1:68150860-68154021  ENSG00000116717
CONAN: Copy Number AnalysisGADD45A 
Mutations
ICGC Data PortalGADD45A 
TCGA Data PortalGADD45A 
Broad Tumor PortalGADD45A
OASIS PortalGADD45A [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGADD45A  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDGADD45A
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch GADD45A
DgiDB (Drug Gene Interaction Database)GADD45A
DoCM (Curated mutations)GADD45A (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)GADD45A (select a term)
intoGenGADD45A
NCG5 (London)GADD45A
Cancer3DGADD45A(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM126335   
Orphanet
MedgenGADD45A
Genetic Testing Registry GADD45A
NextProtP24522 [Medical]
TSGene1647
GENETestsGADD45A
Huge Navigator GADD45A [HugePedia]
snp3D : Map Gene to Disease1647
BioCentury BCIQGADD45A
ClinGenGADD45A
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1647
Chemical/Pharm GKB GenePA28510
Clinical trialGADD45A
Miscellaneous
canSAR (ICR)GADD45A (select the gene name)
Probes
Litterature
PubMed158 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGADD45A
EVEXGADD45A
GoPubMedGADD45A
iHOPGADD45A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Jan 21 16:37:12 CET 2017

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.